The Malaria parasite infects hosts by digesting hemoglobin
and releasing an oxidized form of heme that is toxic for biological membranes.
The malaria parasite can sequester these toxic free hemes to protect
themselves. The antimalarial drug
chloroquine binds to the toxic free heme, enhancing its toxicity, while
interfering with the ability of the parasite to sequester these toxic free
heme. Thus the cytotoxic free heme accumulates to lethal levels in erythrocytes
(red blood cells) that are infected by malaria parasites [28, 29].

In severe malaria, cell-free hemoglobin (that contains that
oxidized form of heme that is toxic), being a POTENT QUENCHER OF NITRIC OXIDE,
are often significantly elevated, causing hemolysis (the rupture or destruction
of red blood cells). Cell-free hemoglobin increases in proportion to disease
severity in malaria and its levels are often correlated to poor clinical
outcome [30].

Critically ill COVID-19 patients often develop acute
respiratory distress syndrome (ARDS). It has been known for a long time that
during critical illness, red blood cells undergo deleterious changes that cause
hemolysis. It is only recently that the release of free heme is also associated
with alveolar inflammation and coagulation in ARDS [39]. A study by Shaver et
al. indicated that the red color observed in the exudates from ARDS patients is
not merely a benign sign of edema, but the presence of CFH and hemolysis [41].
Doctors in the USA are now reporting secretions from COVID-19 patients with
ARDS that are pink in color [50].

A landmark study published by Shaver et. al in 2016 showed
conclusively that elevated cell-free hemoglobin (CFH) in the air space is the
essential driver of lung barrier permeability, inflammation and epithelial
injury in human and experimental animal models of ARDS.

“Free heme” actually describes heme that is NOT STABILIZED
within heme proteins such as hemoglobin or myoglobin. Free heme is in the
unstable FERRIC form that can be transferred to a wide range of heme acceptor
membrane-based proteins and lipids, such as lipoproteins and albumin [31].

Just like the malaria parasite that can protect itself from
the toxic effects of free heme, the human body also has an effective innate
defense system that sequesters cytotoxic cell-free hemoglobin. One of them is haptoglobin, an acute-phase
protein that binds and removes free hemoglobin from the circulation [31]

What does ascorbic
acid have to do with haptoglobin?

Even though haptoglobin can bind cell-free hemoglobin, to maintain these heme in a stable form, haptoglobin must depend on reductants (antioxidants) like ascorbic acid in plasma to maintain the free heme in a reduced, stable, unreactive ferrous (Fe2+) redox state [31, 45]. As demonstrated by Shaver et al. in 2016, free heme without iron ion centers do not inflict as much damage [41]. Heme iron when maintained in the unreactive ferrous (Fe2+) redox state remains stable. Thus the key in controlling the deranged production of cell-free heme in the course of ARDS is to prevent the oxidation of heme to the Ferrous (Fe2+) redox state which is more stable than ferric (Fe3+) redox state. The key to the stability of heme is the maintenance of iron ions in the ferrous (Fe2+) redox state. In the ferric form, hemoglobin have been seen to lose heme to form free heme at substantially higher rates than ferrous forms [47].

The Advantage of the
Haptoglobin Hp2/Hp2 Polymorphism in COVID-19

There are two co-dominant alleles of the Haptoglobin (Hp)
gene. Hp1 and Hp2 have three genotypes:
Hp1/Hp1, Hp1/Hp2 and Hp2/Hp2. Interestingly, a correlation with the severity of
malaria has been observed where 74% of non-severe malaria patients have the
Hp2/Hp2 genotype, while 31% of the carriers of this same Hp2/Hp2 allele
exhibited severe malaria symptoms [44].
Malaria patients with Hp2/Hp2 alleles may have a distinct advantage
where their haptoglobin binds cell-free hemoglobin more effectively.

But why do 31% of patients with the same genotype still
develop severe malaria? The question may
be answered in another study that showed that the Hp2-2 genotype, when compared
to the Hp-1 allele, had lower serum ascorbic levels if they did not supplement
with adequate vitamin C [44]. What does
ascorbic acid have to do with haptoglobin?

Even though haptoglobin can bind cell-free hemoglobin, to
maintain these heme in a stable form, haptoglobin must depend on reductants
(antioxidants) like ascorbic acid in plasma to maintain the free heme in a
reduced, stable, unreactive ferrous
(Fe2+) redox state [31, 45].

Critically ill patients with ARDS are extremely difficult to
oxygenate as their lungs are filled with fluid and cell-free hemoglobin (CFH)
occupying most of the airspace

A Call for Immediate
Attention To The Use of Oral Ascorbic Acid in COVID-19 Patients

The Shanghai Medical Association and the Shanghai city
government now officially endorse the use of vitamin C for the treatment of
COVID-19 infections.

Critically ill patients in sepsis, trauma, burns, or
ischemia/reperfusion injury exhibit extremely low levels of plasma ascorbic
acid [100, 101, 102]. The rapid
depletion of ascorbic acid in plasma of critically ill patients has a direct
impact on the highly conserved eukaryotic transmembrane enzyme known as
Cytochrome b561 (Cytb561). Cytb561 is
ascorbate-dependent. That means this transmembrane enzyme uses ascorbate
EXCLUSIVELY for its role in the recycling of ascorbate [73]. Cytb561 is also
a ferrireductase enzyme responsible for the reduction of iron ions from the
oxidized ferric state to the reduced ferrous state [74]. COVID-19 ARDS patients
are difficult to oxygenate because of systematic destruction of red blood cells
resulting in cell-free heme that have oxidized iron ions in the ferric state.
Under normal conditions, the iron ions in heme can be reduced by Cytb561. So why are COVID-19 patients unable to
maintain stable heme?

Only iron ions in hemoglobin that are in the ferrous form
can bind and transport oxygen. A functional hemoglobin carries four iron ions
and four oxygen molecules. Heme is the protein that carries BOTH iron AND
oxygen [76]. Hemoglobin in red blood
cells are active only when the iron in the heme is in the ferrous reduced
state. In this state, the heme is able
to bind oxygen reversibly. When the iron in heme is oxidized to the ferric state,
the heme is inactivated, and the hemoglobin becomes cell-free hemoglobin that
can cause hemolysis and ARDS in COVID-19 [32].

Without adequate ascorbic acid, heme will rapidly oxidize
and become cell-free hemoglobin. This is
the reason why even young adults in good health and no underlying health
conditions can develop ARDS quickly upon COVID-19 infection [50, 57].

Sodium ascorbate is the form used in all intravenous Vitamin
C applications. The extremely low pH of
ascorbic acid (1.0 to 2.5 at 25 °C, 176 g/L in water) renders it unsuitable for
intravenous injections [80]. All
intravenous ascorbic acid has to be adjusted with buffers to raise pH between
5.5 to 7.0, using sodium bicarbonate [79, 81, 82]. When ascorbic acid is
combined with sodium bicarbonate, sodium ascorbate is created. Hospitals in China and the rest of the world
treat COVID-19 patients with IV C in the
molecular form of sodium ascorbate.
Clinical trials conducted on Vitamin C also use IV C in the form of
sodium ascorbate [83].

It is entirely possible that the sodium ascorbate molecule
may not be in the preferred form that is utilized by our REDOX systems. There has actually been no evidence that
compare side-by-side the difference in results of plasma concentration from
oral ascorbic acid and sodium ascorbate (both IV C and oral), until the
ground-breaking paper released by Owen Fonorow and Steve Hickey on March 13th,
2020 [94].

Fonorow and Hickey exploited this feature and used glucose
meters to measure minute-by-minute results of the two different forms of
vitamin C – ascorbic acid and sodium ascorbate in different combinations of
oral/oral and oral/IV C. The results
from their study are truly remarkable and should be considered as a landmark
moment in orthomolecular medicine due to the way their observations could be
interpreted [94]. When 10 grams of ascorbic acid was ingested orally, compared
to 11.3 grams of sodium ascorbate (to account for additional weight of sodium
in the compound) taken by mouth, Fonorow
and Hickey obtained a totally UNEXPECTED result showing that oral ascorbic acid
is absorbed more efficiently and in higher quantities than sodium ascorbate.

A common misunderstanding about ascorbic acid absorption in
the intestines is that there is an upper limit of about 200 milligrams, above
which, the body would not be able to transport and utilize the molecule. This
is the reason why intravenous delivery is the preferred method as it is
believed to be able to provide a higher bioavailability.

If you look at the oral/IV C chart above, what do you
observe? There is a distinct spike within 2 to 8 minutes after a single
ingestion of 10 g ascorbic acid. The
highest level is more than DOUBLE that achieved by IV C at the same minute
mark. Why would the body absorb ascorbic acid better than sodium ascorbate?

This remarkable study by Fonorow and Hickey (March 2020) not
only showed that oral ascorbic acid is fully absorbed and utilized in high
quantities, it also revealed the true nature of ascorbic acid as a REDOX
molecule.

COVID-19 patients should be afforded the most efficacious
treatment using oral supplementation of ascorbic acid to reduce hypoxia and
lower cell-free hemoglobin, the main cause for ARDS in COVID-19.

The combined oral ascorbic acid AND intravenous sodium
ascorbate treatment may confer COVID-19 patients the best of both worlds.

The following supplementation guide for oral ascorbic acid
is offered as informational purposes only, and should NOT be considered as
MEDICAL ADVICE.

Initial onset of
symptoms:

3 to 5 g in one dose, followed by 1 g every 30 to 60 mins
for the following 3 hours. Repeat this cycle until symptoms subside.

Milder cases:

2 to 5 g in one dose, followed by 1 g every hour for the
following 4 – 6 hours. Repeat this cycle until symptoms subside.

Severe/critical
cases:

10 g in one dose, followed by 2 g every 15 to 30 mins for the following 2 hours. Repeat
this cycle until symptoms improve.

Stomach Acidity

Patients exhibiting stomach discomforts can be given acidic
beverages together with oral ascorbic acid.
Lower pH will facilitate faster absorption. High pH in stomach acids can
slow or even prevent speedy absorption of ascorbic acid. Examples of acidic beverages may include
fresh squeezed lemon/lime in water, apple cider vinegar (1 tbs in 2-3 oz water).

Importance of Sodium
ions in Ascorbic Acid Transport

The transport of ascorbic acid is dependent upon the sodium
electrochemical gradient generated across the plasma membrane by Na+/K+ ATPase.
Theoretically, ascorbate should significantly reduce quenching of NO, raising
NO levels, thus stabilizing blood pressure.

Inhibition of SVCT by
Flavonoids

The flavonoid quercetin has been demonstrated to inhibit transport
of ascorbate by SVCT1. Supplementation of quercetin may need to be reconsidered
when using oral ascorbic acid during COVID-19 treatment.

Ascorbic Acid
Recommendations for Children

Children infected by COVID-19 should, under normal
circumstances, recover quickly. However, they may be asymptomatic and have high
transmissibility. Upon infection
children should be given oral ascorbic acid in the following dosages:

Ages Under 9

Initial dose – 200 mg per 10 lb. body weight

Subsequent doses – 100 mg per 10 lb. body weight

Follow the time schedule under mild cases for adults. If
symptoms worsen, change to the time schedule for severe cases.

Ages Between 10 – 15

Initial dose – 300 mg per 10 lb. body weight

Subsequent doses – 200 mg per 10 lb. body weight

Follow the time schedule under mild cases. If symptoms
worsen, change to the time schedule for severe cases.

Above 15 – treat as
adult

In conclusion, with proper attention to social distancing,
adequate nutrition, sleep, exercise and supplementation with ascorbic acid and
melatonin, in time, COVID-19 may actually become ‘just another flu’ after
all.

[8] SCMP Lung
Damage_Coronavirus: some recovered patients may have reduced lung function and
are left gasping for air while walking briskly, Hong Kong doctors find | South
China Morning Post https://www.scmp.com/news/hong-kong/health-environment/article/3074988/coronavirus-some-recovered-patients-may-have

[9] Macintyre CR. On a knife’s edge of a COVID-19 pandemic:
is containment still possible? Public Health Res Pract. 2020;30(1):3012000.
https://doi.org/10.17061/phrp3012000

[89] A furin cleavage site was discovered in the S protein
of the 2019 novel coronavirus
https://www.researchgate.net/publication/338804501_A_furin_cleavage_site_was_discovered_in_the_S_protein_of_the_2019_novel_coronavirus

[90] The spike glycoprotein of the new coronavirus 2019-nCoV
contains a furin-like cleavage site absent in CoV of the same clade –
https://www.ncbi.nlm.nih.gov/pubmed/32057769

[99] Relation between plasma ascorbic acid and mortality in
men and women in EPIC-Norfolk prospective study: a prospective population study
– The Lancet https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04128-3/fulltext